Terauchi Mikio, Kajiyama Hiroaki, Yamashita Mamoru, Kato Mikihiko, Tsukamoto Hirohisa, Umezu Tomokazu, Hosono Satoyo, Yamamoto Eiko, Shibata Kiyosumi, Ino Kazuhiko, Nawa Akihiro, Nagasaka Tetsuro, Kikkawa Fumitaka
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya, 466-8550, Japan.
Clin Exp Metastasis. 2007;24(5):329-39. doi: 10.1007/s10585-007-9070-1. Epub 2007 May 9.
Loss of E-cadherin triggers peritoneal dissemination, leading to an adverse prognosis for most patients with epithelial ovarian carcinoma (EOC). Because TWIST mainly regulates the epithelial-to-mesenchymal transition and is one of the E-cadherin repressors, we investigated the possibility that TWIST expression affects peritoneal metastasis of EOC using siRNA technique. In the present study, we showed a correlation between TWIST expression and EOC cellular morphology. Furthermore, we demonstrated that the suppression of TWIST expression in EOC cells (HEY) alters the cellular morphology from a fibroblastic and motile phenotype to an epithelial phenotype, and inhibits the adhesion of these cells to mesothelial monolayers. To investigate the mechanism by which down-regulation of TWIST leads to inhibition of adhesion to mesothelial cells (MCs), expression of adhesion molecules (CD29, CD44 and CD54) were observed. Moreover, matrix metalloproteinase 2 and membrane type 1 matrix metalloproteinase, important markers associated with invasive and metastatic potential, were remarkably reduced. This findings suggests that reduced expression of TWIST suppresses the multistep process of peritoneal dissemination (detachment from the primary lesion, adhesion to MCs and invasion of MCs) and may be a potential therapeutic target for the treatment of this carcinoma.
E-钙黏蛋白的缺失会引发腹膜播散，导致大多数上皮性卵巢癌（EOC）患者预后不良。由于TWIST主要调控上皮-间质转化，且是E-钙黏蛋白的抑制因子之一，我们利用小干扰RNA技术研究了TWIST表达影响EOC腹膜转移的可能性。在本研究中，我们发现TWIST表达与EOC细胞形态之间存在相关性。此外，我们证明抑制EOC细胞（HEY）中TWIST的表达会使细胞形态从成纤维细胞样的运动表型转变为上皮表型，并抑制这些细胞与间皮单层细胞的黏附。为了研究TWIST下调导致对间皮细胞（MCs）黏附抑制的机制，我们观察了黏附分子（CD29、CD44和CD54）的表达。此外，与侵袭和转移潜能相关的重要标志物基质金属蛋白酶2和膜型1基质金属蛋白酶也显著降低。这一发现表明，TWIST表达降低可抑制腹膜播散的多步骤过程（从原发灶脱离、黏附于MCs以及侵袭MCs），可能是治疗这种癌症的一个潜在治疗靶点。
